Tannate dry powder formulations

ABSTRACT

Dry powder tannate compositions containing bioactive agents, tannic acid, dispersants, and viscosity modifying agents are disclosed. Specifically, the bioactive agents are antihistamines, decongestants, antitussives, and anticholinergics. The dry powder formulations can further include pharmaceutically acceptable excipients. The dry powder formulations exhibit increased stability for extended shelf life. Bioactive agent tannate salts remain suspended for at least two weeks following formation of the suspension in a pharmaceutically acceptable aqueous liquid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119 to U.S. Ser. No.61/366,348 “Tannate Dry Powder Formulations” filed Jul. 21, 2010 byThomas Jeffrey Bryant, the contents of which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention generally relates to tannate powder formulationscontaining bioactive agents, tannic acid, dispersing agents, andviscosity modifying agents, and methods of making and using thereof.

BACKGROUND OF THE INVENTION

Due to the hydrophobicity of tannic acid-drug complexes, tannate saltsderived from the reaction of a bioactive agent with tannic acid havedecreased solubility in aqueous solutions compared to the free base orother salt forms of the bioactive agent. The relatively poor solubilityof the tannate salt of the bioactive agent can make it suitable forsustained release over prolonged periods of time. Extended or sustainedreleased formulations can improve patient compliance by reducing thenumber of required doses and providing therapeutically effective amountsof the bioactive agents over an extended period of time.

Phenylephrine tannate compositions are used as decongestants alone or incombination with antihistamines such as chlorpheniramine tannate andpyrilamine tannate. Solid dosage phenylephrine tannate compositions aredescribed in U.S. Pat. No. 5,599,846. Solid phenylephrine tannate andchlorpheniramine tannate combination compositions are described in U.S.Pat. No. 6,037,358. U.S. Patent Application No. 2008/0125453 describessuspensions additionally including an antitussive.

U.S. Patent Application No. 2005/0202080 describes a wet granulationprocess for preparing solid dosage formulations containing tannate saltsof bioactive agents.

However, degradation of both dry powder bioactive agent tannate blendformulations and bioactive agent tannate suspension formulations canoccur. Factors which contribute to the instability of tannatecompositions include temperature fluctuation and stress. Manyantihistamine tannate compounds undergo decomposition when exposed toprolonged temperatures at or above 50° C. Therefore, preparationsrequiring heat may lead to degradation and impurities, thereby requiringadditional purification steps to comply with quality control guidelinesto ensure that consistent therapeutic levels of bioactive agent arepresent in the dosage formulations. Furthermore, it is known in the artthat traditionally prepared liquid suspensions and moist blends oftannate salts readily oxidize upon standing at ambient temperatures forextended periods of time, such as during storage, leading todiscoloration, degradation, and/or formation of impurities.

U.S. Pat. Nos. 5,663,415; 5,599,846; and 7,001,886 describe an“isopropanol” route for the preparation of antihistamine tannate soliddosage formulations, which involve a bioactive agent tannate suspensionintermediate. However, the yield of this process is often unsatisfactoryby industrial manufacturing standards, generally only around 70%,including 2-5% by weight that corresponds to decomposition productswhich cannot be removed. The purity of these compositions is generallybetween 85-90%, even though the intermediate suspension is usedrelatively immediately, i.e. within twelve to twenty-four hours of beinggenerated.

Three general methods of preparing suspension formulations of bioactivetannate salts are described in the art. In the first method, describedin U.S. Pat. No. 6,287,597, tannate salts of bioactive agents andaccompanying excipients are suspended in a pharmaceutically acceptableliquid. In the second method, described in U.S. Pat. No. 7,273,623,bioactive agents and tannic acid, and optionally an anti-clumping agent,are reacted in the presence of a pharmaceutically active liquid,spontaneously forming the tannate salt of the bioactive agent. In thethird method, described in U.S. Application No. 2005/0020509, apharmaceutically acceptable liquid containing the salt or free base of abioactive active ingredient is added to a pharmaceutically acceptableliquid containing a dispersing agent and tannic acid.

Dispersing agents are used in suspension formulations to preventclumping. The dispersing agents used in the bioactive agent tannatesuspensions described above are magnesium aluminum silicate and xanthamgum. Xantham gum is used as a dispersing agent in the commercialmanufacturing process of either suspension dosage forms or transientlyformed suspensions prepared during the manufacture of solid dosageforms. However, in order to disperse a suspension effectively withoutthe formation of clumps, formulations using xantham gum as a dispersantrequire the application of high shear. A number of bioactive agents aresensitive to shear stress, and the use of high speed mixing equipmentcan lead to degradation. In addition, formulations including bioactiveagents, tannic acid, and metals, present in dispersants such asmagnesium aluminum silicate, are capable of forming an insoluble complexthat renders the bioactive agent insoluble and therefore unable to beefficiently absorbed by the body. Finally, metal ions can catalyzereactions, such as oxidation or hydrolysis reactions, which degrade theactive agents. None of the above-mentioned suspension formulationsinclude a discussion of stability or shelf-life upon long-term storage.

There is a need for dry powder formulations containing bioactive agentsand tannic acid with extended shelf-lives that do not undergo chemicaldegradation due to oxidation, stress during manufacture, temperaturevariations, and/or equilibration between tannate and other salt formsupon suspension. There is a further need for stable bioactive agenttannate suspension formulations derived from stable dry powderformulations.

It is therefore an object of the present invention to provide stable drypowder formulations of tannic acid, bioactive agents, dispersing agents,and viscosity modifying agents with improved shelf-life. The dry powderformulations should be stable for two weeks to 12 months, morepreferably up to 24 months, most preferably up to 36 months. Suspensionsformed from the dry powder formulations are also stable for extendedperiods of time, and can be prepared by the pharmacist or patient priorto use. The suspensions should be stable for at least two weeks to 12months, most preferably for at least 16 months.

The suspension formulations disclosed herein should exhibit reducedvariability in bioactive agent content between batches such thatbioactive agents can consistently be delivered in therapeuticallyeffective amounts.

SUMMARY OF THE INVENTION

Dry powder drug formulations of antitussives, antihistamines,decongestants and/or anticholinergics, tannic acid, dispersing agents,and viscosity modifying agents that have improved shelf-life aredisclosed. As used herein, improved shelf-life means that the percentdegradation of the one or more bioactive agents is less than 5%, lessthan 4%, less than 3%, less than 2%, or less than 1% after a period ofat least two weeks, three weeks, four weeks, one month, six weeks, twomonths, three months, six months, twelve months, eighteen months,twenty-four months, thirty months, or thirty-six months.

Suspensions of the dry powder formulations in water, or otherpharmaceutically acceptable solvent or cosolvents, also have improvedshelf-life due to the inclusion of dispersing agents and viscositymodifying agents in the dry powder formulation. Suspensions formed fromthe dry powder formulations disclosed herein are stable over a period oftime of at least two weeks, three weeks, four weeks, one month, sixweeks, two months, three months, four months, six months, eight months,ten months, twelve months, or sixteen months.

In one embodiment the dry powder formulation contains phenylephrinehydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate,tannic acid, dispersants, and viscosity modifying agents. Suspensionscan be formed by either a pharmacist or the patient prior to use.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Antihistamine” as generally used herein refers to histamine H₁ receptorantagonists.

“Antitussive” as generally used herein refers to a cough suppressantthat elevates the threshold for coughing.

“Bioactive agent” as generally used herein refers to pharmaceuticalagents containing functional groups suitable for forming tannic salts.These require a basic functional group, such as an amine, to react withtannic acid and form a salt.

“Decongestant” as generally used herein refers to a compound which is anα-adrenergic agonist. Decongestants cause vasoconstriction in the mucosaof the respiratory tract which leads to decongestive properties.

“Degradation” as generally used herein refers to change or changes inthe chemical structure, molecular formula, and/or molecular weight ofthe bioactive agent. Degradation can be an increase in mass as a resultof reactions between one or more bioactive agents, other components, orcombinations thereof. Alternatively, degradation can be a decrease inmass. Degradation of a bioactive agent can be determined by methodsknown to those skilled in the art. For example, high performance liquidchromatography (HPLC) can be coupled to a fluorescence or UV detector todetermine peak purity. Degradation of bioactive agents by these methodswill typically be detected as a broadened peak or the appearance ofadditional peaks, when compared with the trace of the parent bioactiveagent. HPLC can also be coupled with mass spectrometry (HPLC/MS orHPLC/MS/MS) to determine sample purity and/or the degradation products.Degradation of bioactive agents will typically manifest as peaks andmass fragments corresponding to the degradation products that differfrom the peak and/or mass of the parent bioactive agent.

“Dispersing agent” and “dispersant,” used interchangeably herein,generally refer to a chemical which improves separation of particles andprevents settling or clumping when introduced into a suspension.

“Dry powder” as generally used herein refers to solid granules which areessentially free of solvent, such as water. The dry powder can be theproduct of mixing constituent dry powders. The dry powder can alsoresult from removing the solvent, drying, or otherwise dessicating anyliquid solution, slurry, paste, or suspension containing solidcomponents.

“Stable dry powder” as generally used herein refers to a dry powderformulation that does not degrade at 25° C. and 60% relative humidityover a shelf-life period of at least two weeks, three weeks, four weeks,one month, six weeks, two months, three months, six months, twelvemonths, eighteen months, twenty-four months, thirty months, orthirty-six months. For example, a dry powder is considered stable if thepercent degradation of the one or more bioactive agents is less than 5%,less than 4%, less than 3%, less than 2%, or less than 1% as measured byhigh performance liquid chromatography (HPLC). Stable dry powders do notexhibit the following characteristics when compared to an equivalentfreshly prepared dry powder formulation: visual discoloration, increasein moisture content greater than 5%, and/or increase in microbialcontent greater than 5%. Upon suspension, stable dry powder formulationsshould not exhibit sedimentation, decreased dispersability, increases ordecreases in pH greater than 1.0, preferably 0.5, pH units, andflocculation, when compared to suspensions of an equivalent freshlyprepared dry powder formulation.

“Pharmaceutically acceptable liquid” as generally used herein refers toone or more solvents, such as water or alcohol, used for processing orformulation of the dry powder formulation.

“Stable suspension” as generally used herein refers to a homogenoussuspension of an agent or agents in a pharmaceutically acceptableliquid, preferably water, which remains uniformly dispersed for a periodof at least 24, 30 hours, 36 hours, or 48 hours at 25° C. and 60%relative humidity. For example, a suspension is considered stable if thepercent degradation of the one or more bioactive agents is less than5-10%, preferably less than 5%, less than 4%, less than 3%, less than2%, or less than 1% as measured by high performance liquidchromatography (HPLC). Stable suspensions also do not exhibit thefollowing characteristics when compared to an equivalent freshlyprepared suspension formulation: visual discoloration and increase inmicrobial content. Stable suspension formulations should not exhibitsedimentation, decreased dispersability, increases or decreases in pHgreater than 1.0, preferably 0.5, pH units, and flocculation, whencompared to freshly prepared suspensions of an equivalent dry powderformulation.

“Suspension” as generally used herein refers to a heterogeneous fluidcontaining solid particles sufficiently large for sedimentation.

“Tannate salt” as generally used herein refers to a complex of a basiccompound and tannic acid.

“Tannic acid” as generally used herein refers to compounds with acentral polyol core whose hydroxyl groups have been esterified withphenolic benzoic acid derivatives. The central polyol core is preferablyglucose.

II. Dry Powder Formulations

The dry powder formulations contain one or more bioactive agents, tannicacid, dispersants, viscosity modifying agents, and, optionally, one ormore additional pharmaceutically acceptable excipients.

A. Bioactive Agents

Bioactive agents may be therapeutic, prophylactic, and/or diagnosticagents. The bioactive agents can be in the form of the free base or apharmaceutically acceptable salt. Preferred counterions includebitartrate, maleate, citrate, chloride, bromide, fluoride, iodide,acetate, and sulfate. The following are preferred therapeutics.

1. Antihistamines

Antihistamines, classified as H₁ receptor antagonists, are used for theprophylaxis and relief of symptoms of hypersensitivity reactions such asallergic rhinitis, allergic conjunctivitis, urticaria, pruritus,sinusitis, angioedema, and anaphylaxis.

There are two types of antihistamines: first generation and secondgeneration. The older antihistamines (first generation antihistamines)are associated with sedative and anti-muscarinic effects. These olderantihistamines are distinguished from the newer (second generation)antihistamines which are essentially devoid of sedative effects.

In one embodiment, the antihistamine is selected from a non-exclusivelist of first generation antihistamines including brompheniramine,chlorpheniramine, dexbrompheniramine, dexchlorpheniramine,carbinoxamine, clemastine, diphenhydramine, pyrilamine, tripelennamine,tripolidine, methdilazine, bromodiphenhydramine, promethazine,azatadine, cyproheptadine, diphenylpyraline, doxylamine, trimeprazine,phenindamine, hydroxyzine, ketotifen, tazifylline, meclazine, setastine,oxatomide, levocarbastine, lodoxamide, pheniramine, propiomazine,emedastine, flunarizine, meclozine, mefenidramine, methylsulfate andmepyramine.

In one embodiment, the antihistamine is in the free base form. Inanother embodiment, the first or second generation antihistamine is asalt.

In one embodiment, the antihistamine is present in a dry powderformulation from about 0.5% to about 10.0% w/w (% weight/weight), morepreferably in an amount from about 0.5% to about 5.0% w/w, mostpreferably in an amount of about 1.5% w/w.

In one embodiment, the antihistamine is present in a suspensionformulation from about 0.05% to about 5.00% w/v (% weight/volume),preferably in an amount from about 0.05% to about 0.2% w/v (%weight/volume), more preferably in an amount of about 0.12% w/v (%weight/volume).

In one embodiment, the antihistamine is the free base ofchlorpheniramine,3-(p-chlorophenyl)-3-(2-pyridyl)-N,N-dimethylpropylamine. In a preferredembodiment, the antihistamine is a salt of chlorpheniramine, preferablychlorpheniramine maleate. In one embodiment, the chlorpheniraminemaleate is present in a dry powder formulation from about 0.5% to about10% w/w (% weight/weight), more preferably from about 0.5% to about 5.0%w/w, most preferably about 1.5% w/w.

In another embodiment, chlorpheniramine maleate is present in asuspension formulation in an amount from about 0.05% to about 5.00% w/v(% weight/volume), preferably in an amount from about 0.05% to about0.20% w/v (% weight/volume), more preferably in an amount of about 0.12%w/v (% weight/volume).

In another embodiment, the antihistamine is fexofenadine, loratadine,descarboethoxyloratadine, norastemizole, desmethylastemizole,cetirizine, acrivastine, ketotifen, temelastine, ebastine, epinastine,mizolastine, and setastine, astemizole, levocetirizine, rupatadine,mizolastin, noberastine or mequitazine.

2. Decongestants

Decongestants typically act on sympathomimetic targets, such asα-adrenergic receptors. The result is vasoconstriction which leads todecongestive properties.

In one embodiment, the decongestant is phenylephedrine, pseudoephedrine,levo-methamphetamine, naphazoline, oxymetazoline, phenylpropanolamine,propylhexedrine, Synephrine tetrahydrozoline, cyclopentamine,epinephrine, fenoxazoline, levonordefrin, mephentermine, metizoline,norepinephrine, tramazoline, tuaminoheptane, or tymazoline.

In one embodiment, the decongestant is the free base form.

In another embodiment, the decongestant is a salt.

In one embodiment, the decongestant is present in a dry powderformulation in an amount from about 1.0% to about 20.0% w/w (%weight/weight), more preferably in an amount from about 2.0% to about10.0% w/w, most preferably in an amount of about 2.5% w/w.

In another embodiment, the decongestant is present in a suspensionformulation in an amount from about 0.15% to about 5.00% w/v (%weight/volume), preferably in an amount from about 0.15% to about 2.00%w/v (% weight/volume), more preferably in an amount of about 0.20% w/v(% weight/volume).

In one embodiment, the decongestant is the free base of phenylephrine,(R)-(−)-3-Hydroxy-α-(methylaminomethyl)benzyl alcohol. In oneembodiment, the decongestant is a salt of phenylephrine. In a preferredembodiment, the phenylephrine is present as the phenylephrinehydrochloride (HCl) salt.

In one embodiment, phenylephrine hydrochloride is present in a drypowder formulation in an amount from about 1.0% to about 20.0% w/w (%weight/weight), preferably in an amount from about 2.0% to about 10.0%w/w, more preferably in an amount of about 2.5% w/w.

In one embodiment, phenylephrine HCl is present in a suspensionformulation in an amount from about 0.10% to about 5.00% w/v (%weight/volume), preferably in an amount from about 0.10% to about 2.00%w/v (% weight/volume), more preferably in an amount of about 0.20% w/v(% weight/volume).

3. Antitussives

Antitussives, or cough suppressants, are compounds that elevate thethreshold for coughing. In one embodiment, the antitussive iscarbetapentane, dextromethorphan, codeine, hydrocodone, oxycodone, ormorphine.

In one embodiment, the antitussive is present as the free base form. Inanother embodiment, the antitussive is a salt.

In one embodiment, the antitussive is present in a dry powderformulation in an amount from about 1.0% to about 20.0% w/w (%weight/weight), preferably in an amount from about 2.0% to about 15.0%w/w, more preferably in an amount of about 3.8% w/w.

In one embodiment, the antitussive is present in a suspension from about0.20% to about 5.00% w/v (% weight/volume), preferably in an amount fromabout 0.20% to about 3.00% w/v (% weight/volume), more preferably in anamount of about 0.30% w/v (% weight/volume).

In one embodiment, the antitussive is the free base of dextromethorphan,(9S,13S,14S)-3-Methoxy-17-methylmorphinan.

In another embodiment, the antitussive is a salt of dextromethorphan. Ina most preferred embodiment, the antitussive is dextromethorphanhydrobromide (HBr).

In one embodiment, dextromethorphan hydrobromide is present in a drypowder formulation in an amount from about 1.0% to about 20.0% w/w (%weight/weight), preferably in an amount from about 2.0% to about 15.0%w/w, more preferably in an amount of about 3.8% w/w.

In one embodiment, dextromethorphan HBr is present in a suspensionformulation in an amount from about 0.520% to about 5.00% w/v (%weight/volume), preferably in an amount from about 0.20% to about 3.00%w/v (% weight/volume), more preferably in an amount of about 0.30% w/v(% weight/volume).

4. Anticholinergics

Anticholiergics block the action of the neurotransmitter acethycholineand inhibit parasympathetic nerve impulses. Anticholinergics encompasstwo classes of antagonists: antimuscarinics and antinicotinics.Antimuscarinics operate on muscarinic receptors and primarily blockpost-ganglionic parasympathetic receptors. Antinicotinics operate onnicotinic receptors found in the autonomic ganglia and motor end platesin the parasympathetic system. Both classes affect involuntary movementsof smooth muscle tissue and are useful in treating a variety ofdisorders including irritable bowel syndrome, asthma, bronchitis,Parkinson's disease, and bradycardia. Anticholinergics are also used asanaesthetics, antispasmodics, and mydriatic agents.

The acetylcholine receptor antagonists which be employed in the presentformulations are known to those skilled in the art. U.S. Pat. Nos.5,011,853 and 5,552,407 describe acetylcholine receptor antagonists. Inone embodiment, the anticholinergic is selected from the list including,but not limited to, atropine, scopolamine, homatropine, atropine,methscopolamine, methylatropine, ipratropium, methylecgonidine (MEG),mecamylamine, benactyzine, benztropine, trihexyphenidyl, biperiden,procyclidine, benzetimide, dexetimide, dicycloverine, tolterodine,oxybutynin, pirenzepine, telenzepine, tiotropium, combinations thereof,and pharmaceutically acceptable derivatives thereof.

In one embodiment, the anticholinergic is present in a dry powderformulation in an amount from about 0.2% to about 3.0% w/w (%weight/weight), more preferably in an amount from about 0.3% to about2.0% w/w, most preferably in an amount of about 0.35% w/w.

In one embodiment, the anticholinergic is present in a suspension in anamount from about 0.01% to about 0.3% w/v (% weight/volume), preferablyin an amount from about 0.02% to about 0.2% w/v (% weight/volume), morepreferably in an amount of about 0.025% w/v (% weight/volume).

In one embodiment, the anticholinergic is the free base ofmethscopolamine,7(S)-(1α,2β,4β,5α,7β)-7-(3-Hydroxy-1-oxo-2-phenylpropoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0]nonane.In another embodiment, the anticholinergic is a salt of methscopolamine.In a preferred embodiment, the anticholinergic is methscopolaminenitrate.

In one embodiment, methscopolamine nitrate is present in a dry powderformulation in an amount from about 0.2% to about 3.0% w/w (%weight/weight), more preferably in an amount from about 0.3% to about2.0% w/w, most preferably in an amount of about 0.35% w/w.

In one embodiment, methscopolamine nitrate is present in a suspensionformulation in an amount from about 0.01% to about 0.3% w/v (%weight/volume), preferably in an amount from about 0.02% to about 2.0%w/v (% weight/volume), more preferably in an amount of about 0.025% w/v(% weight/volume).

B. Tannic Acid

Naturally occurring tannic acid contains a mixture of compounds producedfrom Turkish or Chinese nutgall that has a complex non-uniformchemistry. The compounds are considered to be secondary metabolites, andhave a molecular weight between 500 Daltons and 5,000 Daltons. Tannicacid is a pale tan powder having a decomposition point of 210-215° C.and is highly soluble in water and alcohols. Tannins are structurallycomplex phenol-rich polymers which can be further divided into twoclasses: hydrolyzable tannins and condensed tannins.

Hydrolyzable tannins, or tannic acids, are composed of gallic acid orits condensation product, composed of ellagic acid esterified to thehydroxyl groups of a carbohydrate monomer. As the name implies,hydrolyzable tannins have ester bonds which are readily saponified undermildly acidic or basic conditions to give the parent carbohydrate andfunctionalized phenolic benzoic acids.

In one embodiment, D-glucose serves as the central component, with thehydroxyl groups esterified (or partially esterified) with functionalizedphenolic benzoic acids. In a preferred embodiment, tannic acid containsat least three hydroxyl groups of the glucose monomer which have beenesterified. In the most preferred embodiment, tannic acid contains allfive hydroxyl groups of the glucose monomer which have been esterified.Tannic acid can be naturally or synthetically derived.

In one embodiment, tannic acid is present in a dry powder formulation inan amount from about 2.5% to about 50.0% w/w (% weight/weight),preferably in an amount from about 103.0% to about 30.0% w/w, morepreferably in an amount of about 6.0% w/w.

In one embodiment, tannic acid is present in a suspension formulation inan amount from about 0.20% to about 10.0% w/v (% weight/volume),preferably in an amount from about 0.30% to about 5.00% w/v (%weight/volume), more preferably in an amount of about 0.5% w/v (%weight/volume).

C. Dispersants

The dispersant prevents clumping and aggregation of the tannate saltcomplex under aqueous or solvent conditions and promotes uniformity inthe suspension upon addition of a pharmaceutically acceptable liquid.

In a preferred embodiment, dispersant or dispersants are present in aneffective amount such that the suspension does not coagulate,agglomerate, or flocculate for at least two weeks, three weeks, fourweeks, one month, six weeks, two months, three months, six months,twelve months, eighteen months, twenty-four months, thirty months, orthirty-six months, following suspension of the dry powder formulation.In addition, the quantity of dispersant or dispersants is present in aneffective amount such that the suspension does not sediment or separateinto multiple layers over a period of time of at least two weeks, threeweeks, four weeks, two months, three months, four months, six months,eight months, ten months, twelve months, preferably sixteen months,following suspension of the dry powder formulation.

In one embodiment, the dispersant is a carrageenan compound.Carrageenans are a family of linear sulfated polysaccharides ofD-galactose and 3,6-anhydro D-galactose which are extracted from redseaweeds. Members of the carrageenan family, including kappa, iota, andlambda carrageenans, are distinguished by the position and number ofsulfate groups present. Iota carageenan is available under the tradenameSeaspen PF by FMC Biopolymer, Philadelphia, Pa.

In another embodiment, the dispersant is maltodextrin. Maltodextrin is apolysaccharide of D-glucose connected by α-linkages, generally three tonineteen glucose units in length, generated from partial hydrolysis ofstarch.

In yet another embodiment, a combination of dispersants is used. In aparticular embodiment, a combination of carrageenan and maltodextrin isused.

In other particular embodiments, the one or more dispersants does notcontain magnesium aluminum silicate. In other particular embodiments,the one or more dispersants does not contain magnesium aluminum silicateand/or xantham gum.

In one embodiment, the dispersant(s) is present in a dry powderformulation in an amount from about 5.0% to about 50.0% w/w (%weight/weight), preferably in an amount from about 10.0% to about 40.0%w/w, more preferably in an amount of about 35.0% w/w.

In one embodiment, the dispersant or dispersants are present in asuspension formulation in an amount from about 0.50% to about 10.0% w/v(% weight/volume), preferably in an amount from about 0.75% w/v to about35.00% w/v. In some preferred embodiments, the dispersant or dispersantsare present in a suspension formulation in an amount between 0.50%-1.0%,0.50%-1.5%, 0.50%-2.0%, 0.50%-2.5%, 0.50%-3.0%, or 0.50%-5.0% w/v. Inthe most preferred embodiment, the dispersant or dispersants are presentin the suspension formulation in an amount of about 3.0% (%weight/volume).

D. Viscosity Modifying Agents

In preferred embodiments, the formulations include a viscosity modifyingagent which stabilizes the suspension. In the most preferred embodiment,the viscosity modifying agent is propylene glycol alginate. Propyleneglycol alginate is an ester product of the reaction between propyleneoxide and alginic acid, in which some of the carboxyl groups on alginicacid are esterified with propylene glycol. The remaining carboxyl groupscan be neutralized with an appropriate alkali and/or remain freecarboxyl groups. Propylene glycol alginate is also known as1,2-propane-diol ester of alginic acid, hydroxypropyl alginate, andpropane 1,2-diol alginate. Propylene glycol alginate is sold under thetradename Protanal® Ester SD-LB, which is available from FMC Biopolymer,Philadelphia, Pa.

Alginates are polyuronic acids which are major components of the cellwalls of brown seaweed. Alginates have valuable rheological propertieswhich can be varied to a great extent by varying the degree ofpolymerization of the polysaccharide and the ionic environment.Alginates can provide suspensions having a range of viscosities andcolloidal properties for various pharmaceutical applications.

In one embodiment, the viscosity modifying agent(s) is present in a drypowder formulation in an amount from about 3.0% to about 50.0% w/w (%weight/weight), preferably in an amount from about 5.0% to about 40.0%w/w, more preferably in an amount of about 25.0% w/w.

In one embodiment, the viscosity modifying agent or agents are presentin a suspension formulation in an amount from about 0.50% w/v to about10.0% w/v (% weight/volume), preferably in an amount from about 0.75%w/v to about 5.00% w/v. In some preferred embodiments, the viscositymodifying agent or agents are present in a suspension formulationbetween 0.50%-1.0%, 0.50%-1.5%, 0.50%-2.0%, 0.50%-2.5%, or 0.50%-3.0%w/v. In the most preferred embodiment, the viscosity modifying agent oragents are present in the suspension formulation in an amount of about2.00% (% weight/volume).

In a preferred embodiment, one or more viscosity modifying agents arepresent in an effective amount such that the suspension exhibits optimalviscosity properties for at least two weeks, three weeks, four weeks,one month, six weeks, two months, three months, four months, six months,eight months, ten months, twelve months, preferably sixteen months,following suspension of the dry powder formulation. In one embodiment,the optimal viscosity of the suspension is between 1000 cPs and 7000cPs, more preferably between 2000 cPs and 5000 cPs, and most preferablybetween 2000 cPs and 4000 cPs.

The viscosity and physical appearance of suspension formulations areinfluenced by the ratio of both dispersant (such as carrageenan) andviscosity modifying agent (such as propylene glycol alginate). Therelative concentration of both components affect the ability of asuspension to resist separation over time and display the optimalviscosity properties, namely between 1000 cPs and 7000 cPs, morepreferably between 2000 cPs and 5000 cPs, and most preferably between2000 cPs and 4000 cPs.

Keeping the amount of viscosity modifying agent constant, suspensionsthat contain one or more dispersants in a concentration that is too lowwill result in separation. Suspensions containing one or moredispersants in a concentration that is too high will result in asuspension that has a heightened amount of solids, such that shakingdoes not give a dispersed suspension.

Keeping the amount of dispersant constant, suspensions that contain oneor more viscosity modifying agents in a concentration that is too lowwill not have the desired viscosity characteristics, namely a viscosityabove 2000 cPs. Suspensions containing one or more viscosity modifyingagents in a concentration that is too high will have viscosities greaterthan 4000 cPs.

In one embodiment, the ratio of dispersant to viscosity modifying agentin a suspension formulation is about 0.5%-5.0% (% w/v) dispersant toabout 1.0%-3.0% (% w/v) viscosity modifying agent. In a more preferredembodiment, the ratio is about 0.5%-3.0% (% w/v) dispersant to about 2%(% w/v) viscosity modifying agent. In the most preferred embodiment, theratio is about 2.0% dispersant (% w/v) to about 3.0% (% w/v) viscositymodifying agent. In the preferred embodiments, the dispersant iscarrageenan (Seaspen PF) and the viscosity modifying agent is propyleneglycol alginate (Protanal Ester SD-LB).

E. Dry Powder Excipients

Dry powder formulations may be prepared using a pharmaceuticallyacceptable carrier composed of materials that are considered safe andeffective and may be administered to an individual without causingundesirable biological side effects or unwanted interactions. Thecarrier is all components present in the pharmaceutical formulationother than the active ingredient or ingredients. As generally usedherein “carrier” includes, but is not limited to, diluents, binders,lubricants, disintegrators, fillers, plasticizers, pigments, colorants,stabilizing agents, glidants, surfactants, humectants, plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,solubilizers, bioavailability enhancers, pH adjusting agents,celluloses, crystallization inhibitors, wetting agents, and combinationsthereof.

Examples of suitable lubricants include, but are not limited to,magnesium stearate, calcium stearate, stearic acid, glycerol behenate,polyethylene glycol, talc, and mineral oil.

Disintegrants facilitate dosage form disintegration, or “breakup,” afteradministration, and generally include, but are not limited to, starch,sodium starch glycolate, sodium carboxymethyl starch, sodiumcarboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch,clays, cellulose, alginine, gums or cross linked polymers, such ascross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactionswhich include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents. Suitable anionic surfactants include, but are not limitedto, those containing carboxylate, sulfonate and sulfate ions. Examplesof anionic surfactants include sodium, potassium, and ammonium salts oflong chain alkyl sulfonates and alkyl aryl sulfonates such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumdodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. Cationic surfactants include, but are not limited to,quaternary ammonium compounds such as benzalkonium chloride,benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples ofnonionic surfactants include ethylene glycol monostearate, propyleneglycol myristate, glyceryl monostearate, glyceryl stearate,polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates,polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylenetridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401,stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodiumN-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate,myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

The powder may also contain nontoxic auxiliary substances such as dyes,pH buffering agents, preservatives, and sweeteners.

The most preferred excipients and their respective amounts, when presentin a dry powder, are: sodium alginate (Seaspen PF), 15-25% (% w/w);silicon dioxide (Cab-o-sil 5-MP), 0.5%-2.5% (% w/v); maltodextrin(Maltrin QD M585), 10.0-20.0% (% w/w); polyvinylpyrrolidone (PovidoneK30), 2-10% (% w/w); polyethylene glycol (PEG 3350), 2-10% (% w/w);Sucralose, 0.5-4.0% (% w/w); sodium benzoate, 0.5-4.0% (% w/w); citricacid, 0.5-4% (% w/w); sodium citrate, 0.5-3.0% (% w/w); and dye,0.03-1.5% (% w/w).

The most preferred excipients and their respective amounts, whensuspended in a pharmaceutically acceptable liquid, most preferablywater, are: sodium alginate (Seaspen PF), 1.0%-5.0% (% w/v); silicondioxide (Cab-o-sil M-5P), 0.05%-1.0% (% w/v); maltodextrin (Maltrin QDM585), 0.50%-3.0% (% w/v); polyvinylpyrrolidone (Povidone K30),0.10%-1.0% (% w/v); polyethylene glycol (PEG 3350), 0.10%-1.0% (% w/v);Sucralose, 0.05%-0.60% (% w/v); sodium benzoate, 0.05%-0.30% (% w/v);citric acid, 0.05%-0.60% (% w/v); sodium citrate, 0.05%-0.30% (% w/v);and dye, about 0.01%.

III. Methods of Preparing Dry Powder Formulations

A. Formation of the Dry Powder for Storage

The tannic acid, one or more bioactive agents, one or more dispersingagents, and one or more viscosity modifying agents are mixed in theirdry, non-reactive states to obtain a uniform blend. Optionally, anysolid excipients can also be added at this point and concurrently mixed,to form a uniform blend. The bioactive agent should be in a stable form,such as the free base or acid. The tannic acid:drug ratio is from about0.5:1 to about 3:1 ratio to obtain proper tannate salt conversion uponsuspension of the dry powder.

The ingredients are mixed with a suitable powder blender with low shear.Such blenders are well known in the art and include, but are not limitedto, V-blenders, paddle blenders, planetary blenders, or ribbon blenders.The ingredients are blended for from about 5 minutes to about 30minutes.

Next, a container is filled with the dry powder for storage. Suitablecontainers include, but are not limited to, 1 oz., 4 oz., 8 oz., or 16oz. bottles. Other suitable containers include sealed bags. In apreferred embodiment, the container is suitable for storage of the drypowder such that the powder is stable for at least 2 weeks, morepreferably at least 1 month, more preferably six weeks, more preferablyat least 2 months, more preferably at least 3 months, more preferably atleast 4 months, more preferably at least 5 months, more preferably atleast 6 months, more preferably at least 7 months, more preferably atleast 8 months, more preferably at least 9 months, more preferably atleast 10 months, more preferably at least 11 months, more preferably aleast 12 months, more preferably up to 24 months, most preferably up to36 months prior to suspension.

Stability can be measured by methods known to those skilled in the artincluding moisture content, microbial content, appearance, color,dispersability, pH, and purity. The percent degradation of the one ormore bioactive agents of the dry powder formulation should be less than5% at 25° C. and 60% relative humidity and/or 40° C. and 75% relativehumidity in long-term storage. In a preferred embodiment, the percentdegradation of the one or more bioactive agents is less than 5%, lessthan 4%, less than 3%, less than 2%, or less than 1% as measured by highperformance liquid chromatography (HPLC).

In another embodiment, the stored dry powder does not significantlychange in original color compared to a freshly prepared dry powderformulation, as determined by UV spectroscopy or visual observation. Ina preferred embodiment, the stored dry powder is not brown in color.

In another embodiment, moisture content of the stored dry powder doesnot increase more than 5%, more than 4%, more than 3%, more than 2%, ormore than 1%.

In another embodiment, microbial content of the stored dry powder doesnot increase. In another embodiment, the pH of a suspension of thestored dry powder does not differ more than 1.0, preferably 0.5, pHunits from that of a suspension of freshly prepared dry powder.

In another embodiment, a suspension of stored dry powder does notcontain solidified globular material formed by flocculation,agglomeration, or coagulation, but instead consists of finely dispersedparticulate material. The presence of globular material can bedetermined visually or by methods known to those skilled in the artincluding multiple light scattering coupled with vertical scanning. Inone embodiment, the dry powder does not form floccules, agglomerates, orother solidified globular material.

B. Formation of Suspensions

A suspension of the dry powder can be prepared by the pharmacist,prescribing physician, or patient prior to use. To avoid difficultiesassociated with degradation and impurities, it would be beneficial todelay formation of a suspension dosage as long as possible. The drypowder will be present in the container in an amount which will yieldthe appropriate dosage (mg/mL) when mixed with either 15 mL (1tablespoon), 4 oz, 8 oz., or 16 oz. of a solvent, such as water, andshaken well for about 10 to about 30 seconds. This step converts thebioactive agents to their tannate salt form without clumping.

In preferred embodiments, the suspension is stable, and can be used overa period of time of at least two weeks, three weeks, four weeks, twomonths, three months, four months, six months, eight months, ten months,twelve months, preferably sixteen months. Stability can be measured bymethods known to those skilled in the art including moisture content,microbial content, appearance, color, dispersability, pH, and purity.

The percent degradation of the one or more bioactive agents of thesuspension formulation should not degrade more than 5% at 25° C. and 60%relative humidity and/or 40° C. and 75% relative humidity in long-termstorage. In a preferred embodiment, the percent degradation of the oneor more bioactive agents is less than 5%, less than 4%, less than 3%,less than 2%, or less than 1% as determined by high performance liquidchromatography (HPLC).

In one embodiment, the stable suspension does not visually separate toform two or more layers. In another embodiment, the stable suspensiondoes not have sediment particulates at the bottom of the container. Inanother embodiment, the stable suspension does not significantly changein original color compared to a freshly prepared suspension, asdetermined by UV spectroscopy or visual observation. In a preferredembodiment, the stable suspension is not brown in color.

In another embodiment, moisture content does not increase by more than5%, more than 4%, more than 3%, more than %, or more than 1%. In anotherembodiment, microbial content does not increase. In another embodiment,the pH of the suspension does not differ more than 1.0, preferably 0.5,pH units from that of a freshly prepared suspension.

In another embodiment, the stable suspension does not contain solidifiedglobular material formed by flocculation, agglomeration, or coagulation.The presence of globular material can be determined visually or bymethods known to those skilled in the art including multiple lightscattering coupled with vertical scanning. In one embodiment, thesuspension does not form floccules, agglomerates, or other solidifiedglobular material.

The following examples are included to demonstrate preferred embodimentsof the invention. It will be apparent to those of skill in the art thatvariations may be applied to the compositions and methods describedherein without departing from the concept, spirit, and scope of theinvention.

EXAMPLES Example 1 Suspension of a Dry Powder Formulation (1)

A 118 mL suspension was prepared with the following:

Percent weight/volume Ingredient (% w/v) Amount (g) Chlorpheniramine0.12 0.142 maleate Phenylephrine HCl 0.20 0.236 Dextromethorphan HBr0.30 0.354 Tannic Acid 0.47% 0.549 Seaspen PF 1.50% 1.770 Cab-o-sil M-5P0.15% 0.177 Maltrin QD M585 1.50% 1.770 Povidone K30 0.50% 0.590 PEG3350 0.50% 0.590 Protanal Ester SD-LB 2.00% 2.360 Sucralose 0.20% 0.236Sodium Benzoate 0.15% 0.177 Citric Acid 0.20% 0.236 Sodium Citrate 0.10%0.118 Dye 0.01% 0.012 Purified Water 92.11% 108.684 Total 100 118.000

Example 2 Suspension of a Dry Powder Formulation (2)

A 473 mL suspension was prepared with the following:

Percent weight/volume Ingredient (% w/v) Amount (g) Chlorpheniramine0.12% 0.568 maleate Phenyleprine HCl 0.20% 0.946 Dextromethorphan HBr0.30% 1.419 Tannic Acid 0.47% 2.199 Seaspen PF 1.50% 7.095 Cab-o-silM-5P 0.15% 0.710 Maltrin QD M585 1.50% 7.095 Povidone K30 0.50% 2.365PEG 3350 0.50% 2.365 Protanal Ester SD-LB 2.00% 9.460 Sucralose 0.20%0.946 Sodium Benzoate 0.15% 0.710 Citric Acid 0.20% 0.946 Sodium Citrate0.10% 0.473 Dye 0.01% 0.047 Purified Water 92.11% 435.657 Total 100473.000

Example 3 Effect of Varying the Weight Percentages of Dispersant andViscosity Modifying Agent on Viscosity

Suspension formulations with varying amounts of propylene glycolalginate (viscosity modifying agent) and carageenan (dispersant) in 118mL of water were prepared with the agents below. The viscosities of thesuspensions were determined at various time points shown below.

Percent weight/volume Percent (% w/v) weight/volume Propylene (% w/v)Glycol Seaspen PF Viscosity (cPs) Sample Alginate (carrageenan) Initial24 h 48 h 1 wks 2 wks 1 2.0 2.5 4524 4132 3889 4008 4127 2 3.0 0.5 94777204 7382 7461 6429 3 1.0 2.5 635 595 555 427 555 4 2.0 0.5 3175 30163135 2738 3016 5 2.0 1.5 3889 3135 2976 3175 2103 6 1.0 1.5 873 397 317595 515 7 3.0 1.5 14320 14090 13850 12660 11430 8 1.0 0.5 2738 833 1111635 595 9 3.0 2.5 17500 10550 12220 14800 15200

Example 4 Physical Characteristics of Dry Powder Suspension Stability

The physical characteristics of the suspension formulations in Example 3were visually observed and measured at various time points. The resultsare shown below.

Physical Characteristics Sample Initial 24 h 48 h 1 wk 2 wks 1uniform^(a) uniform uniform Uniform uniform after scraping^(b,e) 2uniform uniform uniform Uniform uniform 3 uniform uniform uniformuniform uniform 4 uniform uniform uniform uniform uniform 5 uniformuniform uniform uniform uniform 6 uniform separation^(c) separationseparation separation 7 uniform uniform uniform uniform uniform afterscraping^(e) 8 uniform separation separation^(d) separation separation 9uniform uniform uniform uniform uniform after scraping^(e) ^(a)uniformsuspension ^(b)spatula required to remove dried powder from bottom ofcontainer ^(c)two layers of at least 1 mm thickness visually observed^(d)three layers of at least 1 mm thickness visually observed ^(e)waterhad to be added in two portions to generate suspension

Discussion

Examples 3 and 4 illustrate that the viscosity and physical appearanceof suspension formulations are affected by the amount of dispersant(carrageenan) and viscosity modifying agent (propylene glycol alginate).Samples 1, 7, and 9, contained the two highest concentrations ofpropylene glycol alginate (2.0% or 3.0% w/v) and the highestconcentration of carrageenan (2.5% w/v). These samples containedelevated amounts of solids that could not be dispersed by shaking only.Both manual agitation with a spatula and step-wise water addition wererequired to form the suspension. In addition, suspensions 7 and 9exhibited higher than desired viscosities due to the heightenedconcentration of propylene glycol alginate present. Samples 6 and 8contained the lowest concentration of propylene glycol alginate (1.0%w/v) and the two lowest concentrations of carrageenan (0.5% and 1.5%w/v). However, both of these suspension samples separated upon standing.Sample 2 remained uniform, even in the presence of the 3.0% w/vpropylene glycol alginate. However, the viscosity was consistentlygreater than 6000 cPs. Sample 3 also remained uniform throughout theexperiment. However, the viscosity was markedly lower than desired,consistently below 1000. Samples 4 and 5, both made with mid-rangeamounts of both propylene glycol alginate and carrageenan, exhibitedoptimal visual characteristics and viscosity. Neither suspensionseparated up to a period of 2 weeks. In addition, samples 4 and 5 hadoptimal viscosities of between 2000 cPs and 4000 cPs.

1. A dry powder formulation comprising one or more bioactive agents,tannic acid, a high molecular weight polymeric dispersant, and aviscosity modifying agent, wherein the dry powder formulation is stablefor at least two weeks at 25° C. and 60% relative humidity.
 2. Asuspension formulation formed from the dry powder formulation of claim 1and a pharmaceutically acceptable aqueous liquid, wherein the suspensionis stable for at least two weeks following suspension at 25° C. and 60%relative humidity.
 3. The formulation of claim 1, wherein the bioactiveagent is selected from the group consisting of antihistamines,decongestants, antitussives, anticholinergics, and combinations thereof.4. The formulation of claim 2, wherein the bioactive agent is selectedfrom the group consisting of antihistamines, decongestants,antitussives, anticholinergics, and combinations thereof.
 5. Theformulation of claim 3, wherein the antihistamine is present in anamount from about 0.05% to about 5.00% w/v (% weight/volume) uponsuspension in a pharmaceutically acceptable aqueous liquid.
 6. Theformulation of claim 4, wherein the antihistamine is present in anamount from about 0.20% to about 5.00% w/v (% weight/volume) of thesuspension.
 7. The formulation of claim 5, wherein the antihistamine ispresent in about 0.12% w/v (% weight/volume) upon suspension in apharmaceutically acceptable aqueous liquid.
 8. The formulation of claim6, wherein the antihistamine is present in about 0.12% w/v (%weight/volume) of the suspension.
 9. The formulation of claim 3 whereinthe antihistamine is selected from the group consisting ofbrompheniramine, chlorpheniramine, dexbrompheniramine,dexchlorpheniramine, carbinoxamine, clemastine, diphenhydramine,pyrilamine, tripelennamine, tripolidine, methdilazine,bromodiphenhydramine, promethazine, azatadine, cyproheptadine,diphenylpyraline, doxylamine, trimeprazine, phenindamine, hydroxyzine,ketotifen, tazifylline, meclazine, setastine, oxatomide, levocarbastine,lodoxamide, pheniramine, propiomazine, emedastine, flunarizine,meclozine, mefenidramine, methylsulfate, mepyramine, combinationsthereof, and pharmaceutically acceptable salts thereof.
 10. Theformulation of claim 4 wherein the antihistamine is selected from thegroup consisting of brompheniramine, chlorpheniramine,dexbrompheniramine, dexchlorpheniramine, carbinoxamine, clemastine,diphenhydramine, pyrilamine, tripelennamine, tripolidine, methdilazine,bromodiphenhydramine, promethazine, azatadine, cyproheptadine,diphenylpyraline, doxylamine, trimeprazine, phenindamine, hydroxyzine,ketotifen, tazifylline, meclazine, setastine, oxatomide, levocarbastine,lodoxamide, pheniramine, propiomazine, emedastine, flunarizine,meclozine, mefenidramine, methylsulfate, mepyramine, combinationsthereof, and pharmaceutically acceptable salts thereof.
 11. Theformulation of claim 3, wherein the antihistamine is selected from thegroup consisting of fexofenadine, loratadine, descarboethoxyloratadine,norastemizole, desmethylastemizole, cetirizine, acrivastine, ketotifen,temelastine, ebastine, epinastine, mizolastine, and setastine,astemizole, levocetirizine, rupatadine, mizolastin, noberastine,mequitazine, combinations thereof, and pharmaceutically acceptable saltsthereof.
 12. The formulation of claim 4, wherein the antihistamine isselected from the group consisting of fexofenadine, loratadine,descarboethoxyloratadine, norastemizole, desmethylastemizole,cetirizine, acrivastine, ketotifen, temelastine, ebastine, epinastine,mizolastine, and setastine, astemizole, levocetirizine, rupatadine,mizolastin, noberastine, mequitazine, combinations thereof, andpharmaceutically acceptable salts thereof.
 13. The formulation of claim11, wherein the antihistamine is chlorpheniramine maleate.
 14. Theformulation of claim 12, wherein the antihistamine is chlorpheniraminemaleate.
 15. The formulation of claim 3, wherein the decongestant ispresent in an amount from about 0.10% to about 5.00% w/v (%weight/volume) upon suspension in a pharmaceutically acceptable aqueousliquid.
 16. The formulation of claim 4, wherein the decongestant ispresent in an amount from about 0.10% to about 5.00% w/v (%weight/volume) of the suspension.
 17. The formulation of claim 15,wherein the decongestant is present at a concentration of about 0.20%w/v (% weight/volume) upon suspension in a pharmaceutically acceptableaqueous liquid.
 18. The formulation of claim 16, wherein thedecongestant is present at a concentration of about 0.20% w/v (%weight/volume) of the suspension.
 19. The formulation of claim 15,wherein the decongestant is selected from the group consisting ofphenylephedrine, pseudoephedrine, levo-methamphetamine, naphazoline,oxymetazoline, phenylpropanolamine, propylhexedrine, synephrinetetrahydrozoline, cyclopentamine, epinephrine, fenoxazoline,levonordefrin, mephentermine, metizoline, norepinephrine, tramazoline,tuaminoheptane, tymazoline, combinations thereof, and pharmaceuticallyacceptable salts thereof.
 20. The formulation of claim 16, wherein thedecongestant is selected from the group consisting of phenylephedrine,pseudoephedrine, levo-methamphetamine, naphazoline, oxymetazoline,phenylpropanolamine, propylhexedrine, synephrine tetrahydrozoline,cyclopentamine, epinephrine, fenoxazoline, levonordefrin, mephentermine,metizoline, norepinephrine, tramazoline, tuaminoheptane, tymazoline,combinations thereof, and pharmaceutically acceptable salts thereof. 21.The formulation of claim 19, wherein the decongestant is phenylephrinehydrochloride.
 22. The formulation of claim 20, wherein the decongestantis phenylephrine hydrochloride.
 23. The formulation of claim 3, whereinthe antitussive is present in an amount from about 0.25% to about 5.00%w/v (% weight/volume) upon suspension in a pharmaceutically acceptableaqueous liquid.
 24. The formulation of claim 4, wherein the antitussiveis present in an amount from about 0.25% to about 5.00% w/v (%weight/volume) of the suspension.
 25. The formulation of claim 23,wherein the antitussive is present in about 0.3% w/v (% weight/volume),upon suspension in a pharmaceutically acceptable aqueous liquid.
 26. Theformulation of claim 24, wherein the antitussive is present in about0.3% w/v (% weight/volume) of the suspension.
 27. The formulation ofclaim 23, wherein the formulation comprises an antitussive selected fromthe group consisting of carbetapentane, dextromethorphan, codeine,hydrocodone, oxycodone, morphine, combinations thereof, andpharmaceutically acceptable salts thereof.
 28. The formulation of claim24, wherein the formulation comprises an antitussive selected from thegroup consisting of carbetapentane, dextromethorphan, codeine,hydrocodone, oxycodone, morphine, combinations thereof, andpharmaceutically acceptable salts thereof.
 29. The formulation of claim27, wherein the antitussive is dextromethorphan hydrobromide.
 30. Theformulation of claim 28, wherein the antitussive is dextromethorphanhydrobromide.
 31. The formulation of claim 3, wherein theanticholinergic is present in an amount from about 0.01% to about 0.3%w/v (% weight/volume) upon suspension in a pharmaceutically acceptableaqueous liquid.
 32. The formulation of claim 4, wherein theanticholinergic is present in an amount from about 0.01% to about 0.3%w/v (% weight/volume) of the suspension.
 33. The formulation of claim31, wherein the anticholinergic is present in an amount of about 1.50%w/v (% weight/volume) upon suspension in a pharmaceutically acceptableaqueous liquid.
 34. The formulation of claim 32, wherein theanticholinergic is present in an amount of about 1.50% w/v (%weight/volume) upon suspension in a pharmaceutically acceptable aqueousliquid.
 35. The formulation of claim 31, wherein the formulationcomprises an anticholinergic selected from the group consisting ofatropine, scopolamine, homatropine, atropine, methscopolamine,hyoscyamine, methylatropine, ipratropium, methylecgonidine (MEG),mecamylamine, benactyzine, benztropine, trihexyphenidyl, biperiden,procyclidine, benzetimide, dexetimide, dicycloverine, tolterodine,oxybutynin, pirenzepine, telenzepine, tiotropium, clidinium,combinations thereof, and pharmaceutically acceptable salts thereof. 36.The formulation of claim 32, wherein the formulation comprises ananticholinergic selected from the group consisting of atropine,scopolamine, homatropine, atropine, methscopolamine, methylatropine,hyoscyamine, ipratropium, methylecgonidine (MEG), mecamylamine,benactyzine, benztropine, trihexyphenidyl, biperiden, procyclidine,benzetimide, dexetimide, dicycloverine, tolterodine, oxybutynin,pirenzepine, telenzepine, tiotropium, clidinium, combinations thereof,and pharmaceutically acceptable salts thereof.
 37. The formulation ofclaim 35, wherein the anticholinergic is methscopolamine nitrate. 38.The formulation of claim 36, wherein the anticholinergic ismethscopolamine nitrate.
 39. The formulation of claim 1, wherein theconcentration of tannic acid is from about 0.3% to about 5.00% w/v (%weight/volume) upon suspension in a pharmaceutically acceptable aqueousliquid.
 40. The formulation of claim 2, wherein the concentration oftannic acid is from about 0.3% to about 5.00% w/v (% weight/volume) ofthe suspension.
 41. The formulation of claim 1, wherein the dispersantis present in an amount from about 0.50% to about 10.0% w/v (%weight/volume) upon suspension in a pharmaceutically acceptable aqueousliquid.
 42. The formulation of claim 2, wherein the dispersant ispresent in an amount from about 0.50% to about 10.0% w/v (%weight/volume) of the suspension.
 43. The formulation of claim 41,wherein the dispersant is present in an amount from about 0.50% to 3.0%.44. The formulation of claim 42, wherein the dispersant is present in anamount from about 0.50% to 3.0%.
 45. The formulation of claim 1, whereinthe dispersant is carrageenan or maltodextrin.
 46. The formulation ofclaim 1, wherein the viscosity modifying agent is present in an amountfrom about 0.50% to about 10.0% w/v (% weight/volume) upon suspension ina pharmaceutically acceptable aqueous liquid.
 47. The formulation ofclaim 2, wherein the viscosity modifying agent is present in an amountfrom about 0.50% to about 10.0% w/v (% weight/volume) of the suspension.48. The formulation of claim 46, wherein the viscosity modifying agentis present in an amount from about 0.5% to about 2.0% w/v (%weight/volume).
 49. The formulation of claim 47, wherein the viscositymodifying agent is present in an amount from about 0.5% to about 2.0%w/v (% weight/volume).
 50. The formulation of claim 1, wherein theviscosity modifying agent is propylene glycol alginate.
 51. Theformulation of claim 1 further comprising dry powder excipients selectedfrom the group consisting of diluents, binders, lubricants,disintegrators, fillers, plasticizers, pigments, colorants, stabilizingagents, glidants, surfactants, humectants, plasticizers, crystallizationinhibitors, wetting agents, bulk filling agents, solubilizers,bioavailability enhancers, pH adjusting agents, and combinationsthereof.
 52. The formulation of claim 2 further comprising dry powderexcipients selected from the group consisting of diluents, binders,lubricants, disintegrators, fillers, plasticizers, pigments, colorants,stabilizing agents, glidants, surfactants, humectants, plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,solubilizers, bioavailability enhancers, pH adjusting agents, andcombinations thereof.
 53. The formulation of claim 2, wherein theviscosity of the suspension is between about 2000 cPs and about 4000cPs.
 54. The formulation of claim 1, wherein the one or more bioactiveagents present in the dry powder formulation degrades less than about5%, as determined by high performance liquid chromatography, for atleast two weeks at 25° C. and 60% relative humidity for at least 36months.
 55. The formulation of claim 2, wherein the one or morebioactive agents present in the suspension formulation degrades lessthan about 5%, as determined by high performance liquid chromatography,for at least two weeks at 25° C. and 60% relative humidity for at least16 months.
 56. A method for the preparation of stable dry powderformulations, comprising: (a) mixing one or more bioactive agents,tannic acid, a high molecular weight polymeric dispersant, and aviscosity modifying agent, all in their non-reactive dry powder forms,with a low shear blender until uniformly mixed, and (b) filling acontainer with the dry powder, wherein the one or more bioactive agentspresent in the dry powder formulation degrades less than about 5%, asdetermined by high performance liquid chromatography, for at least twoweeks at 25° C. and 60% relative humidity.
 57. A method for thepreparation of a stable suspension of the dry powder formulation ofclaim 51, further comprising: (c) the addition of a pharmaceuticallyacceptable aqueous liquid to the container, wherein the one or morebioactive agents present in the suspension formulation degrades lessthan about 5%, as measured by high performance liquid chromatography,for at least two weeks at 25° C. and 60% relative humidity.
 58. Theformulation of claim 2, wherein ratio of the dispersant and viscositymodifying agent is about 3.0% dispersant (% w/v) to about 2.0% (% w/v)viscosity modifying agent.